MOLECULAR ABNORMALITIES OF MDM-2 IN HUMAN SARCOMAS

MDM-2 is an oncoprotein that seems to function, at least in part, by i nteracting with the p53 protein and modulating its tumor-suppressing a ctivity. The MDM-2 gene codes for p57, p74, p76, p85, and p90 proteins . Overexpression of only the p90 MDM-2 protein has been reported in sa rcomas showing MDM-2 gene amplification. In addition, post-transcripti onal mechanisms have been demonstrated to play a role in the expressio n of MDM-2 proteins. We investigated MDM-2 gene amplification, mRNA an d protein levels in various cases of sarcomas. We found MDM-2 gene amp lification in 12 (26%) of 46 cases of sarcoma: 11 of 13 cases of lipos arcoma and 1 of 6 cases of malignant fibrous histiocytoma. The MDM-2 a mplification correlated with the presence of elevated levels of mRNA a nd protein in the liposarcomas. In sarcomas other than liposarcomas, m RNA was overexpressed in 7 (30%) of 23 cases, without MDM-2 amplificat ion. In 15 (62.5%) of 24 cases of sarcoma and in 1 case of lipoma the MDM-2 protein was overexpressed as shown by Western blot analysis. Int erestingly, p57 not p90 was the most commonly overexpressed MDM-2 prot ein. These data indicate that the molecular abnormalities affecting MD M-2 expression in cases of sarcoma include transcriptional, post-trans criptional, and gene dosage (amplification) mechanisms. Furthermore, o ur findings suggest that MDM-2 p57 protein may be as important as p90 in the pathogenesis of human sarcomas.